Reduction of 11-ketoprogesterone to 3beta-hydroxyallopregnane-11, 20-dione



Patented Aug. 17, 1954 REDUCTION OF 11-KETOPROGESTERONE TO3/3-HYDROXYALLOPREGNANE-11,20-

DIONE 1 Barney J. Magerlein, Kalamazoo, and Robert H. Township,Kalamazoo County, Mich., assignors to The Upjohn Com- Levin, Kalamazoopany, Kalamazoo, Mich.,

I Michigan a corporation of No Drawing, Application March 2, 1953,

, Serial No. 339,916

Claims. (Cl. 260-39145) The novel process may be represented by thefollowing formulae:

wherein the hydrogenation of the, ll-ketoprogesterone in the presence ofa specific catalyst, a platinum catalyst, proceeds in one step to3B-hydroxya1lopregnane-11,20-dione.

While hydrogenation of steroid compounds containing double bonds as wellas keto groups have frequently been carried out, there is no referencein the art showing any method for the reduction of a 3 keto A groupingin almost quantitative yield and in one step to a 35-01- saturatedsteroid or allosteroid. Reduction of double bonds of steroid compoundswithout simultaneous reduction of keto groups is known, a recent examplebeing the hydrogenation of 1105- hydroxyprogesterone to give 11ahydroxypregnane 3,20 dione and 110s. hydroxyallo pregnane-3,20-dione.Similarly, the reduction with hydrogen of a 3-keto group to a S-carbinolgroup in a steroid without concomitant reduction of double bonds isknown. For example, Ruzicka [U. S. Patent 2,168,685] shows reduction of3-keto-A -steroids to 3a-ol-A -steroids by catalytic hydrogenation. Inother hydrogenations of steroids, mixtures of compounds were obtained.For example, W. H. Perlman, J. Biol. Chem. 166, pp. 473-476 (1946)hydrogenated progesterone, obtaining a mixture of compounds apparentlycontaining both the corresponding normal and allo steroid compounds. Inorder to obtain pure compounds instead of mixtures, reduction ofsteroids possessing both keto groups and double bonds was carried out intwo steps. For example, cholestenone, a compound possessing a 3-keto-A-grouping, was hydrogenated to the saturated compound coprostanone inthe presence of a palladium catalyst, and was then hydrogenated tocoprostanol with a platinum cat- 3,11,20 -trione.

alyst in acidic solution (summarized in Fieser and Fieser, NaturalProducts Related to Phenanthrene, 3rd edition, Reinhold PublishingCorporation, New York, N. Y., 1949, page 99). In view of this art, it isconsidered an entirely unexpected and unpredictable result, thatll-ketoprogesterone can be hydrogenated toBIB-hydroxyallopregnane-11,20-dione in nearly quantitative yields and ina single step.

An object of the present invention is to provide a novel process for thehydrogenation of ll-ketoprogesterone in such a manner that the 3-keto-M-grouping thereof is reduced and hydrogenated in one step and thecorresponding 3-hydroxyallosteroid is obtained. A further object of thisinvention is to providea process wherein the abovecited hydrogenationtakes place without concomitant reduction of keto groups in positions 11and 20. Other objects of the invention will be apparent to one skilledin the art to which this invention pertains.

The utility of this process resides in the fact that ll-ketoprogesterone(I) can be hydrogenated in very high yield in one step to 3,8-hydroxyallopregnane 11,20 dione (II) rather than in two steps. Thislatter compound may then be converted to cortisone acetate by a processshown by Kritchevsky et al., J. Am. Chem. Soc. 74, 483 (1952) inconjunction with a process by Djerassi, Nature, 168, 28 (1951).. If inKritchevskys process 3B-hydroxyallopregnane- 11,20-dione is substitutedfor the 3a-hydroxypregnane-11,20-dione,17u-hydroxy-21-acetoxyallopregnane-3,11,20-trione will be obtainedinstead of the 17a-hydroxy-2l-acetoxypregnane- This compound, which isknown in the art, has been converted by bromination, treatment withsodium iodide in acetone and dehydrohalogenation to cortisone acetate byDjerassi et al., Nature, 168, 28 (1951).

The steps necessary to obtain cortisone acetate from 3hydroxyallopregnane 11,20 dione include: treating3-hydroxyallopregnane-11,20- dione with acetic anhydride to obtain36,11,20- triacetoxy-9 (11) ,17 20) -allopregnadiene which, by treatmentwith perbenzoic acid, yields 3,8,11,20- triacetoxy 17(20) oxido 9(11)allopregnene. Hydrolysis of this compound gives3,8,17u-dihydroxyallopregnane-l1,20-dione which by bromination yields35,1711 dihydroxy 21 bromoallopregnane-11,20-dione. Treatment of the 21-bromo compound with potassium acetate gives the corresponding3fi,1'7u-dihydroxy-21-acetoxy pregnane-11,20-dione and oxidationfurnishes the 17a hydroxy 21 acetoxyal1opregnane-3,11,20-

3 trione. Bromination of this compound by Djerassis method results in2,4-dibromo-1'7u hydroxy 21 acetoxyallopregnane 3,11,20- trione, andthis compound, when treated with sodium iodide in acetone, gives the2-iodo-4-bromo- 21acetoxyallopregnane-3,11,20-trione which bysimultaneous dehalogenation and dehydrohalogenation with collidine isconverted to cortisone acetate. Neither the dibromo nor the iodobromosteroid need be isolated in the process. It is obvious that otherutility accrues to the process of the invention as various other usesmay be made of the 3p-hydroxyallopregnane-11,20- dione thereby producedin exceedingly high yield in but a single step operation.

In carrying out the process of the present invention,ll-ketoprogesterone, dissolved in a convenient organic solvent, e. g.,methanol, ethanol, dioxane, ethyl acetate or other like solvent, withmethanol being preferred, is admixed with a platinum catalyst suitablycomprising finely subdivided platinum. The catalyst may be on an inertcarrier, for example, kieselguhr or pumice, alone or associated with apromoter. Reduced platinum dioxide, prereduced by prior reduction ofplatinum dioxide with hydrogen, or by the reduction of platinum dioxidein situ during the hydrogenation and reduction of ll-ketoprogester onemay be utilized. In the preferred embodiment of the invention thecatalyst is prereduced platinum dioxide. The mixture is then shaken.

with hydrogen in a Paar hydrogenator until two moles of hydrogen areabsorbed per mole of 11- ketoprogesterone. The hydrogen pressure ismaintained between about two and seventy pounds per square inch,preferably between about five and 25 pounds per square inch. The timerequired for the absorption may range from one half hour to forty-eighthours. After the termination of absorption, the catalyst is removed byfiltration and the solvent evaporated. The 3/3- hydroxyallopregnane3,11,20 trione thus-obtained may be recrystallized from solvents, suchas ethyl acetate, hexanes mixed with ethyl acetate, and other likesolvents, or used in the crude form for further steps of synthesis.

The following example is given to illustrate the method of the presentinvention and is not to be construed as limiting.

Example.Hydrogena;tton 11-ketoizwogesterone Five hundred milligrams (500milligrams) of ll-ketoprogesterone were dissolved in one hundredmilliliters of C. P. methanol and 300 milligrams of prereduced platinumdioxide (PtOz) added thereto. The mixture was introduced into a Paarhydrogenator and shaken at room. temperature under about ten pounds persquare inch hydrogen pressure for two hours, during which time two molesof hydrogen were absorbed. The catalyst was then removed by filtrationof the suspension and the solvent was evaporated. Four hundred andninety milligrams (490 milligrams) of material equal to a yield of about9'7 percent were obtained. The material was recrystallized from ethylacetate and exhibited a melting point of 187-188 degrees centigrade.Infrared analysis and papergram analysis of this material showed it tobe pure 3/B-hydroxyallopregnane-11,20-dione. Chromic acid oxidation ofthis material gave a quantitative yield of known allopregnane-3,11,20-trione.

In a manner similar to the example, ll-ketoprogesterone was hydrogenatedin ethanol, ethyl acetate, and dioxane solutions at room temperature inthe presence of prereduced platinum dioxide to giveBB-hydroxyallopregnane-11,20-dione in substantially quantitative yield.

It is to be understood that the invention is not to be limited to theexact details shown and described in the example as obviousmodifications and equivalents will be apparent to one skilled in the artand the invention is therefore to be limited only by the scope of theappended claims.

We claim:

1. A process for the production of 3,8-hydroxyallopregnane-l1,20-dionewhich comprises: hydrogenating ll-ketoprogesterone in an organic solventwith hydrogen at a pressure between about two and seventy pounds persquare inch, in the presence of a platinum catalyst, until about twomoles of hydrogen is absorbed, to obtain 35-hydroxyallopregnane-11,20-dione.

2. The process of claim 1 wherein the solvent is methanol.

3. A process for the production of 3p-hydroxyallopregnane-l1,20-dionewhich comprises: hydrogenating ll-ketoprogesterone in an organic solventwith hydrogen at a pressure between about two and seventy pounds persquare inch in the presence of a reduced platinum dioxide catalyst,until about two moles of hydrogen is absorbed, to obtain35-hydroxyallopregnane-11,20- ouone.

4. A process for the production of 3B-hydroxyallopregnane-11,20-dionewhich comprises: hydrogenating ll-ketoprogesterone in an organic solventwith hydrogen at a pressure between about five and 25 pounds per squareinch in the presence of a platinum catalyst prepared by prior reductionof platinum dioxide with hydrogen, until about two moles of hydrogen areabsorbed, to obtain 3fl-hydroxyallopregnane-11,2'0-dione.

5. The process of claim 4 wherein the solvent is methanol.

No references cited.

1. A PROCESS FOR THE PRODUCTION OF 3B-HYDROXYALLOPREGNANE-11,20-DIONEWHICH COMPRISES: HYDROGENATING 11-KETOPROGESTERONE IN AN ORGANIC SOLVENTWITH HYDROGEN AT A PRESSURE BETWEEN ABOUT TWO AND SEVENTY POUNDS PERSQUARE INCH, IN THE PRESENCE OF A PLATINUM CATALYST, UNTIL ABOUT TWOMOLES OF HYDROGEN IS ABSORBED, TO OBTAIN3BHYDROXYALLOPREGNANE-11,20-DIONE.